Increasing use of spinal and regional anesthesia in the clinical setting necessitates the systematic evaluation of the variables associated with those techniques. We have developed a chronic non-human primate model for spinal anesthesia in our laboratory. Use of this model for spinal anesthesia will allow the isolation and control of the variables which relate to the mechanism, efficacy, and safety of spinal anesthesia. This project will adopt a dose response approach to the two least studied variables, i.e., osmolality and concentration. We will study these variables using lidocaine, bupivacaine, 2-chloroprocaine and tetracaine. Specifically, we propose to test two hypotheses: 1) there is an optimal osmolality at which local anesthetics become most effective for spinal anesthesia; 2) the mechanism for osmotic potentiation of spinal anesthesia is not pharmacokinetic. These hypotheses will be tested in our in vivo primate model using three concentrations of the four local anesthetic agents at varying toxicities. Correlation of plasma drug levels with differential neural blockade will further provide test of these hypotheses. The general experimental design provides for the optimization of all the combined effects of osmolality and concentration. This desgn allows us to examine the effect of varying drug concentrations at a given osmolality as well as to examine the effects of varying osmolality at a given concentration. The evaluation of the quality of differential subarachnoid block will be broken down into the motor, sensory, and sympathetic components. Physiological measures will be expressed as averages over time. Quantitative scores of motor, sensory, and sympathetic blockade will be determined every five minutes during the block. The significance of the proposed research rests in a thorough understanding of the mechanism, physiology, and pharmacokinetics of spinal anesthesia.